Exploration of Novel Urolithin C Derivatives as Non-Competitive Inhibitors of Liver Pyruvate Kinase

Umberto Maria Battisti; Leticia Monjas; Fady Akladios; Josipa Matic; Eric Andresen; Carolin H Nagel; Malin Hagkvist; Liliana Håversen; Woonghee Kim; Mathias Uhlen; Jan Borén; Adil Mardinoğlu; Morten Grøtli

doi:10.3390/ph16050668

Exploration of Novel Urolithin C Derivatives as Non-Competitive Inhibitors of Liver Pyruvate Kinase

Pharmaceuticals (Basel). 2023 Apr 28;16(5):668. doi: 10.3390/ph16050668.

Authors

Umberto Maria Battisti^{1

2}, Leticia Monjas^{1

2}, Fady Akladios^{1

2}, Josipa Matic^{1

2}, Eric Andresen¹, Carolin H Nagel¹, Malin Hagkvist¹, Liliana Håversen^{3

4}, Woonghee Kim², Mathias Uhlen², Jan Borén^{3

4}, Adil Mardinoğlu^{2

5}, Morten Grøtli¹

Affiliations

¹ Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96 Gothenburg, Sweden.
² Science for Life Laboratory, KTH-Royal Institute of Technology, SE-171 65 Stockholm, Sweden.
³ Department of Molecular and Clinical Medicine, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
⁴ Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden.
⁵ Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London SE1 9RT, UK.

Abstract

The inhibition of liver pyruvate kinase could be beneficial to halt or reverse non-alcoholic fatty liver disease (NAFLD), a progressive accumulation of fat in the liver that can lead eventually to cirrhosis. Recently, urolithin C has been reported as a new scaffold for the development of allosteric inhibitors of liver pyruvate kinase (PKL). In this work, a comprehensive structure-activity analysis of urolithin C was carried out. More than 50 analogues were synthesized and tested regarding the chemical features responsible for the desired activity. These data could pave the way to the development of more potent and selective PKL allosteric inhibitors.

Keywords: NAFLD; SAR studies; allosteric inhibitors; liver pyruvate kinase; urolithin C.

Abstract

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